WO2005055807A2 - Procedes et compositions pour recherche des predispositions a l'autisme - Google Patents

Procedes et compositions pour recherche des predispositions a l'autisme Download PDF

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WO2005055807A2
WO2005055807A2 PCT/US2004/040444 US2004040444W WO2005055807A2 WO 2005055807 A2 WO2005055807 A2 WO 2005055807A2 US 2004040444 W US2004040444 W US 2004040444W WO 2005055807 A2 WO2005055807 A2 WO 2005055807A2
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autism
seq
gene
primers
sequence
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WO2005055807A3 (fr
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Joseph D. Buxbaum
Nicolas Ramoz
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BEATRICE AND SAMUEL A SEAVER FOUNDATION
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Priority to DE602004030372T priority patent/DE602004030372D1/de
Priority to CA002548590A priority patent/CA2548590A1/fr
Priority to AT04817937T priority patent/ATE490340T1/de
Priority to EP04817937A priority patent/EP1697533B1/fr
Priority to AU2004296804A priority patent/AU2004296804B2/en
Publication of WO2005055807A2 publication Critical patent/WO2005055807A2/fr
Publication of WO2005055807A3 publication Critical patent/WO2005055807A3/fr
Priority to IL176121A priority patent/IL176121A/en
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0356—Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/172—Haplotypes

Definitions

  • the present invention generally relates to autism risk assessment. More specifically, methods and compositions are provided that are useful for estimating risk for having autism.
  • Phenotypic homogeneity provides increased support for linkage on chromosome 2 in autistic disorder.
  • Autism or autistic disorder is a neurodevelopmental disorder characterized by a deficit in verbal and non-verbal communication, impairments in reciprocal social interactions, and patterns of repetitive or stereotyped behaviors and interests (1-3).
  • the sex-ratio is 4: 1 male to female, and the prevalence of the disease is currently thought to possibly be above 1 per 1000 persons (4).
  • Autism appears to be the most highly genetic of the psychiatric disorders as evidenced by the high risk of autism in additional children in families with an autistic child (estimated to be 50 to 100 times greater than that expected by chance) and the concordance rate for monozygotic twins being much higher than that of dizygotic twins (5).
  • Heritability estimates of idiopathic autism are above 90% (6), so much of the disorder can be attributed to a genetic etiology.
  • autism does not follow a simple Mendelian mode of transmission (i.e., dominant or recessive transmission) but is clearly a polygenic disease (4).
  • a commonly accepted genetic model involves several genes (between 5 to 10) that interact to produce the disorder.
  • autism A genetic mutation or variant segregating with autism has yet to be unequivocally identified.
  • Candidate genes for studies of autism range from genes that are thought to play a role in neurodevelopmental pathways, comportment or behavior, such as genes in the serotonergic pathway or reelin (4, 7, 8).
  • a few polymorphisms in several genes have been associated with the disorder in certain studies, but not in others (4, 9-11).
  • Several independent studies involving genome-wide scans have now been published and point to significant linkage between autism and chromosome 2q and 7q regions (4, 12).
  • TBR1 nine candidate genes (TBR1 , GAD1, DLX1, DLX2, cAMP-GEFII, CHN1, CREB2, HOXD1 and NEUROD1) localized across a 30 Mb region of 2q, that are expressed in the central nervous system and encode proteins that play a role in neuronal cells or in neurobiological pathways (16). Variants were observed in TBR1, cAMP-GEFII, CHN1, HOXD1 and NEURODl. However, no evidence was found that any of the candidate genes contributes to autism. In this region, our laboratory, together with the laboratory of Dr.
  • Miriam Meisler has previously investigated the neuronal voltage-gated sodium channels type I, II and III (SCN1A, SCN2A and SCN3A) in 117 multiplex autism families (17). Rare mutations were identified, each in single families, that were not observed in controls. These mutations, while of great interest, are not likely to account for the evidence of linkage observed in this region. There is thus a need to pinpoint genetic variations associated with autism, in order to be able to determine whether individuals are at particular risk for autism, and to determine the risk for autism in offspring of two individuals. Identification of genetic risk factors would also provide tools and information for elucidating the causes of autism. The present invention addresses that need.
  • the invention is directed to method of evaluating an individual for relative genetic risk for autism.
  • the methods comprise determining the individual's genotype at polymorphism sites rs2056202 and/or rs2292813 of the SLC25A12 gene.
  • the presence of a G at either of the two sites indicates an increased risk for autism, and the presence of an increasing number of G's at the sites indicates an increasing risk for autism.
  • the invention is also directed to sets of two primers suitable for use in polymerase chain reaction, useful for the methods identified immediately above.
  • the invention is additionally directed to kits comprising the above-identified primers.
  • the invention is directed to polynucleotides consisting of any of the sequences of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4.
  • the invention is further directed to methods of identifying a form of a genetic polymorphism that is linked to autism.
  • the methods comprise identifying a polymorphism in the SLC25A12 gene and determining whether one form of the polymorphism is present in autistic individuals more than another form. In these embodiments, in the form that is present more often in autism is linked to autism.
  • the invention is directed to eukaryotic cells comprising a transgenic human SLC25A12 gene, and non-human animals comprising those cells. Additionally, the invention is directed to methods of evaluating whether a compound affects autism. The methods comprise contacting the compound with the above described eukaryotic cell, then determining whether the compound affects expression or activity of a product of the SLC25A12 gene. In these embodiments, a compound that affects expression or activity of the product of the SLC25A12 gene affects autism.
  • FIG. 1 is three graphics showing the genomic organization of the autism susceptibility locus on chromosome region 2q24-q33.
  • Panel A shows the genetic and cytogenetic mapping.
  • Panel B shows the organization of positional candidate genes. Arrowhead indicates orientation of transcription.
  • Panel C shows the genomic structure of SLC25A12 gene. Variants identified in the present study are indicated (see text), with the two SNPS focused on in the current study, rs2056202 (13-21A/G) and rs2292813 (I16+70A/G) underlined.
  • FIG. 2 is a table showing the results of a relative risk assessment using polymorphisms of the SLC25A12 gene.
  • the present invention is based on the discovery of an association between certain polymorphisms in the SLC25A12 gene and autism. This discovery enables various compositions and methods for use in various aspects of autism diagnostics, therapeutics, and research.
  • the invention is directed to method of evaluating an individual for relative genetic risk for autism.
  • the methods comprise determining the individual' s genotype at polymorphism sites rs2056202 and/or rs2292813 of the SLC25A12 gene.
  • the presence of a G at either of the two sites indicates an increased risk for autism, and the presence of an increasing number of G's at the sites indicates an increasing risk for autism.
  • any human can be tested using these embodiments, and these methods can also be used to determine the potential risk of the offspring of two individuals for autism, based on the identified genotype of the parents at the relevant polymorphism.
  • the invention is not narrowly limited to any particular method for determining the individual's genotype at the relevant polymorphic sites; the skilled artisan could chose and apply an appropriate method for any particular application without undue experimentation.
  • the genotype is determined by single strand conformation polymorphism, denaturing high-performance liquid chromatography, DNA Invader, and/or polymerase chain reaction amplification followed by sequencing. See, e.g., Example 1.
  • preferred primers for amplifying the appropriate regions are comprise SEQ ID NO: 5 and SEQ ID NO: 6 (for amplifying the relevant region of rs2056202 [these primers amplify SEQ ID NO:l or SEQ ID NO:2, depending on the polymorphic form present]) or SEQ ID NO:7 and SEQ ID NO:8 (for amplifying the relevant region of rs2292813 [amplifying SEQ ID NO:3 or SEQ ID NO:4]).
  • the invention is also directed to sets of two primers suitable for use in polymerase chain reaction, useful for the methods of determining an individual's risk for autism, as described above.
  • Preferred primer sets are SEQ ID NO:5 and SEQ ID NO:6, for amplifying the relevant region of rs2056202, and SEQ ID NO:7 and SEQ ID NO:8, for amplifying the relevant region of rs2292813.
  • any other primers that are specific for either of the relevant regions of the SLC25A12 gene could also be used, and can be designed without undue experimentation.
  • the invention is directed to kits comprising at least one set of primers suitable for use in polymerase chain reaction (PCR). The set of primers in these kits amplifies polymorphism site rs2056202 or rs2292813, or both of the SLC25A12 gene.
  • kits can also comprise instructions for using the set(s) of primers to evaluate an individual for relative genetic risk for autism by determining the genotype of the polymorphic sites re2056202 and/or re2292813 of the SLC25A12 gene.
  • kits can also comprise other ingredients such as buffers, enzymes and the like, for performing PCR and/or analysis of the PCR product(s).
  • the invention is additionally directed to PCR products amplified using any of the above-described primer sets. Nonlimiting examples of these PCR products include SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4.
  • the invention is further directed to methods of identifying a form of a genetic polymorphism that is linked to autism.
  • the methods comprise identifying a polymorphism in the SLC25A12 gene and determining whether one form of the polymorphism is present in autistic individuals more than another form. In these embodiments, in the form that is present more often in autism is linked to autism.
  • the polymorphisms identified by these methods can also be used to determine the risk of an individual to autism.
  • Nonlimiting examples of procedures to conduct these methods are provided in the Example 1.
  • Genetic polymorphisms identified by the above procedure that are associated with autism can also be used to evaluate an individual for relative genetic risk for autism. Since this invention includes the discovery that the SLC25A12 gene is associated with autism, the skilled artisan would understand that cells and multicellular organisms comprising the human SLC25A12 gene are useful for autism research. Thus, the instant invention is also directed to eukaryotic cells comprising a transgenic human SLC25A12 gene.
  • these eukaryotic cells are particularly useful when the transgenic SLC25A12 gene comprises the sequence of SEQ ID NO: 2 and/or SEQ ID NO:4, since those sequences are within SLC25A12 genes associated with autism.
  • the cell is a yeast cell, or a mammalian cell, such as a brain cell.
  • the cell can also be within a living mammal, such as a transgenic mammal transfected with the gene.
  • the invention is directed to non-human animals comprising the above described eukaryotic cells.
  • the non-human animal of these embodiments is a mammal.
  • the invention is also directed to methods of evaluating whether a compound affects autism.
  • the methods comprise contacting the compound with any of the above eukaryotic cells and determining whether the compound affects expression or activity of a product of the SLC25A12 gene.
  • a compound that affects expression or activity of the product of the SLC25A12 gene affects autism.
  • the compounds useful for these embodiments can be a small organic or inorganic molecule or a 1 macromolecule such as an antibody, an aptamer, an siRNA, an antisense compound, etc.
  • Preferred embodiments of the invention are described in the following examples. Other embodiments within the scope of the claims herein will be apparent to one skilled in the art from consideration of the specification or practice of the invention as disclosed herein. It is intended that the specification, together with the examples, be considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow the examples.
  • Example summary Objective Autism/autistic disorder (MLM #209850) is a complex, largely genetic psychiatric disorder.
  • MLM #209850 a susceptibility locus for autism to chromosome region 2q24-q33 (MDVI #606053).
  • MDVI #606053 chromosome region 2q24-q33
  • Method Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying genetic variants in exons and flanking sequence within candidate genes, in unrelated subjects showing linkage to 2q24-q33, and comparing the frequency of the variants between subjects and controls.
  • SNPs single nucleotide polymorphisms
  • APC1 mitochondrial aspartate/glutamate carrier
  • TDT transmission disequilibrium test
  • the aim of the present study was to identify an autism susceptibility gene in the 2q31 region.
  • a systematic screen for genetic variants in affected individuals identified linkage and association between autism and single nucleotide polymorphisms in the SLC25A12 gene.
  • ADI-R Diagnostic Interview-Revised (19). Individuals meeting ADI-R criteria for autism (19) or borderline autism (13) were defined as affected. The cohort (18) and research diagnosis definitions used in the current study (13) have been described. The entire cohort of 411 families included blood samples from more than 2000 individuals, including 720 affected individuals (671 with autism and 49 with borderline autism), and available parents and sibs. The 411 families included 274 multiplex (typically affected sibling-pairs) and 137 trio families. DNA from blood samples or transformed cells were either isolated as detailed in Buxbaum et al., 2001, or provided by the AGRE repository. Mutation screening. To investigate the involvement of positional candidate genes in autism, we performed a two-stage screen.
  • exonic and flanking DNA from 35-47 patients from 38 autistic families linked to the chromosome 2q24-q33 region were screened for genetic variants by single strand conformation polymorphism (SSCP) and denaturing high-performance liquid chromatography (DHPLC).
  • SSCP single strand conformation polymorphism
  • DPLC denaturing high-performance liquid chromatography
  • Primers to amplify exons and flanking regions of positional candidate genes were designed using primer3 software (http://www-genome.wi. ⁇ r ⁇ it.edu/cgi-bir ⁇ primer/primer3_www.cgi) and are available on request.
  • the forward and reverse primers were chosen to produce amplicons of less than 500 bp. Larger exons, in particular the last exons of the genes, were divided over several amplicons, each with a size of less than 500 base pairs.
  • Primers within flanking introns were situated 26 to 186 bp from the exons. A total of 82 exons of 9 genes were analyzed, using 93 amplicons with an average size of ca. 310 nucleotides.
  • forward primers were labeled using 100 ⁇ Ci [ ⁇ P32]-ATP and 10 units of T4 polynucleotide kinase, according to the protocol provided by Invitrogen. Amplification was carried out using Ampli-Taq Gold Polymerase (Applied Biosystems) in a final volume of 10 ⁇ l, consisting of 10 ng of genomic DNA, 10 mM Tris-HCl, 50 rnM KC1, 2.5mM MgCl, 100 M dNTPs, 10 ⁇ M radioactively-labeled forward and unlabeled reverse primers, and 0.5 units of Taq Polymerase.
  • Genotyping was carried out using the biplex DNA Invader method (Third Wave Technologies).
  • the Invader assay is based on the hybridization of an oligonucleotide probe that completely matches a DNA target and the subsequent cleavage of the overlapping structure by
  • Cleavase VIII resulting in a target-specific product that is recognized by a fluorescence resonance energy transfer (FRET) cassette (20).
  • FRET fluorescence resonance energy transfer
  • Specific oligonucleotide probes corresponding to wild type and mutated SNPs are associated with specific fluorophores, enabling simultaneous detection of both DNA sequences in a single well.
  • diluted aliquots of the PCR products were combined with Invader mix solution (Third Wave Technologies), and incubated for the cleavage reaction in a thermal cycler (PTC- 100, MJ Research). The reaction product was then analyzed on a fluorescence plate reader (CytoFluor Series 4000, PerSeptive Biosystems) using the appropriate parameters of excitation and emission for each fluorophore.
  • TDT-GENEHUNTER GENEHUNTER version 2.1, compiled to run on the Unix environment of Mac OS X
  • S-TDT (21) program http://genomics.med.upenn.edu/spielman/TDT.htm
  • GADl glutamate decarboxylase 1
  • FLJ13096 FLJ13984, LOC130672, and FLJ23462, recently identified as duodenal cytochrome b
  • HAT-1 histone acetylase-1
  • Figure 1C presents the five variants of the SLC25A12 gene identified in 47 affected subjects linked to the chromosome 2q24-q33 region.
  • the two polymorphism meeting criteria in the first stage rs2056202 (I3-21A G) and rs2292813 (I16+70A/G), are G/A variants in flanking intronic sequence located 21 bp upstream of exon 4 and 70 bp downstream of exon 16, respectively.
  • G1418A changes arginine 473 to glutamine, while the C99T variant is silent.
  • G1418A is a new SNP, not reported in the NCBI dbSNPs database, located in a region conserved across mammalian species, but the amino acid glutamine is observed in mice. The final variant appears in the 3' untranslated region (UTR).
  • UTR 3' untranslated region
  • TDT Transmission Disequilibrium Test
  • G*G 102 45 22.10 3X10- 6 54 19 66.52 3X10- 16 48 26 11.92 6X10- 4
  • two-locus TDT showed disequilibrium of transmission of the four observed haplotypes for both one affected per family
  • a genotype relative risk was also estimated for individuals carrying one or two copies of the risk alleles (the G alleles in both cases) for either rs2056202 or rs2292813. Results are given in FIG. 2. Those results show that the relative risk increases with increasing G alleles at either polymorphic site. It should also be noted that genotype relative risk estimates in TDT studies such as this underestimate the true genotype relative risk. See Risch, Theoret. Pop. Biol. 60, 215-220 (2001). Therefore, the true autism risk for the genotypes indicated in FIG. 2 is likely to be considerably higher than indicated.
  • the objective of the present work was to identify a susceptibility gene for autism in chromosome region 2q24-q33.
  • Preferential transmission of the G allele for both SNPs was found in 197 informative families.
  • linkage was found between autism and the SNPs by TDT and by non-parametric and parametric analyses.
  • the SLC25A12 gene contains 18 exons spreading over about 110 kilobases (kb) and is expressed primarily as 2.9 and 3.2kb mRNA species, predominantly in skeletal muscle, heart and brain (25).
  • SLC25A12 cDNA has an open reading frame of 2037 bp encoding a 678 amino acids protein that is a calcium-dependent mitochondrial aspartate/glutamate carrier (AGCl).
  • AGCl calcium-dependent mitochondrial aspartate/glutamate carrier
  • the subcellular localization of protein is exclusively mitochondrial.
  • the amino-terminal half of AGCl contains five putative EF hands that are able to bind Ca2+, while the carboxy-terminal half harbors the aspartate/glutamate exchanger function.
  • AGCl is critically involved in the activity of the malate/aspartate NADH shuttle, catalyzing the electrogenic exchange of aspartate for glutamate and a proton, as well as in the urea cycle (26).
  • SLC25A12 gene is the only form of the mitochondrial aspartate/glutamate carrier expressed in neurons and neural stem cells (27). Protein levels increased during neuronal differentiation and are correlated with an increase in the malate/aspartate NADH shuttle activity.
  • SLC25A12 mRNA and the AGCl protein are widely expressed in adult mouse CNS, particularly in neural nuclei in the brainstem (27). It has been suggested that the enrichments of AGCl in specific neurons could reflect a tonic activity of these neurons. Dysfunction of this protein, or altered expression of this protein, may lead to an alteration in mitochondrial function and ATP synthesis.
  • SLC25A13 Mutations in SLC25A13 gene confers adult-onset type II citrullinemia (CTLN2, MIM#603471), an autosomal recessive disease caused by a deficiency of argino-succinate synthetase with clinical features included enuresis diarrhea, tremors, lethargy, mental retardation and psychiatric disorders. Although confirmation of the association between autism and SLC25A12 is required, it is believed that SLC25A13 could be a candidate autism susceptibility gene on chromosome 7. For both SNPs, the allele associated with autism corresponds to a common allele. One must consider that in complex disorders with multiple interacting genes, the prevalence of the susceptibility alleles may be quite high.
  • SLC25A12 locus as a susceptibility gene for autism we are currently searching for additional genetic markers across the 110 kb region containing this gene, using both extant databases and sequencing in the patients we are studying, particularly of conserved non-coding regions. To date, more than 90 SNPs encompassing the SLC25A12 gene have been identified in the public databases, with at least 20 SNPs harboring a heterozygosity rate over 0.1. None of these appear in conserved non-coding regions. We are also carrying out expression studies of AGCl.
  • Example 2 Further association of AGC1/SLC25A12 with autism.
  • Example 1 we reported the linkage and association between autism and the presence of two single nucleotide polymorphisms (SNPs), both within the same gene, SLC25A12/AGC1, an aspartate/glutamate exchanger.
  • SNPs single nucleotide polymorphisms
  • SEQ ID NO:5 forward primer for amplifying rs2056202 GTTACCCTGAGCTACAGTT
  • SEQ ID NO:6 reverse primer for amplifying rs2056202 TCAGATCCCAAATAAGCAG
  • SEQ ID NO:8 reverse primer for amplifying rs2292813 GCATTGGTCTTAAAGGTTCTGTCT

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Abstract

La présente invention concerne des procédés et des compositions permettant, non seulement de rechercher chez un individu les prédispositions génétiques à l'autisme, mais aussi d'identifier une forme d'un polymorphisme génétique lié à l'autisme, et enfin de vérifier si un composé affecte l'autisme.
PCT/US2004/040444 2003-12-05 2004-12-03 Procedes et compositions pour recherche des predispositions a l'autisme Ceased WO2005055807A2 (fr)

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Application Number Priority Date Filing Date Title
US10/581,140 US20070248956A1 (en) 2003-12-05 2004-12-03 Methods and Compositions for Autism Risk Assessment
DE602004030372T DE602004030372D1 (de) 2003-12-05 2004-12-03 Verfahren zur Bestimmung des relativen genetischen Risikos für Autismus
CA002548590A CA2548590A1 (fr) 2003-12-05 2004-12-03 Procedes et compositions pour recherche des predispositions a l'autisme
AT04817937T ATE490340T1 (de) 2003-12-05 2004-12-03 Verfahren zur bestimmung des relativen genetischen risikos für autismus
EP04817937A EP1697533B1 (fr) 2003-12-05 2004-12-03 Procédé pour déterminer le risque génétique relatif à l'autisme
AU2004296804A AU2004296804B2 (en) 2003-12-05 2004-12-03 Methods and compositions for autism risk assessment
IL176121A IL176121A (en) 2003-12-05 2006-06-05 Autism Risk Assessment Methods

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US60/527,630 2003-12-05

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CA2548590A1 (fr) 2005-06-23
EP1697533A2 (fr) 2006-09-06
ES2355242T3 (es) 2011-03-24
DE602004030372D1 (de) 2011-01-13
WO2005055807A3 (fr) 2006-03-09
US20070248956A1 (en) 2007-10-25
EP1697533A4 (fr) 2008-03-05
IL176121A (en) 2013-11-28
ZA200605466B (en) 2008-03-26
AU2004296804A1 (en) 2005-06-23
AU2004296804B2 (en) 2011-04-14

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